Modular Degradable Hydrogels Based on Thiol-Reactive Oxanorbornadiene Linkers

Abstract

Oxanorbornadiene dicarboxylate (OND) reagents are potent Michael acceptors, the adducts of which undergo fragmentation by retro-Diels–Alder reaction at rates that vary with the substitution pattern on the OND moiety. Rapid conjugate addition between thiol-terminated tetravalent PEG and multivalent ONDs yielded self-supporting hydrogels within 1 min at physiological temperature and pH. Erosion of representative hydrogel formulations occurred with predictable and pH-independent rates on the order of minutes to weeks. These materials could be made non-degradable by epoxidation of the OND linkers without slowing gelation. Hydrogels prepared with OND linkers of equal valence had comparable physical properties, as determined by equilibrium swelling behavior, indicating similar internal network structure. Diffusion and release of entrained cargo varied with both the rate of degradation of PEG-OND hydrogels and the hydrodynamic radius of the entrained species. These results highlight the utility of OND linkers in the preparation of degradable network materials with potential applications in sustained release.

Albumin-Oxanorbornadiene Conjugates Formed ex Vivo for the Extended Circulation of Hydrophilic Cargo

“…The rate of fragmentation varies with the identity of the parent OND, and can be tuned over a wide range under physiological conditions. 10,11 Fragmentation-resistant epoxyoxanorbornene (EONB) derivatives can be prepared by epoxidation of OND linkers at the electron-rich alkene. 10,12 We have previously described the use of this linker technology to achieve conjugation and release of fluorescent cargo from bovine and human serum albumins, with release half-lives ranging from 40 minutes to nearly 1 week under simulated physiological conditions.…”

“…10,11 Fragmentation-resistant epoxyoxanorbornene (EONB) derivatives can be prepared by epoxidation of OND linkers at the electron-rich alkene. 10,12 We have previously described the use of this linker technology to achieve conjugation and release of fluorescent cargo from bovine and human serum albumins, with release half-lives ranging from 40 minutes to nearly 1 week under simulated physiological conditions. 11 We describe herein the first application of this chemistry in vivo to modulate the pharmacokinetic parameters of gadolinium chelators as model hydrophilic cargos.…”

“…26,27 However, our design potentially circumvents the need of preparing macromolecular conjugates in vitro and cleavage of OND adducts occurs by a pH insensitive mechanism. 10 This binding and release of endogenous long-circulating carriers may prove useful in the context of optimizing the pharmacokinetics of drug molecules or diagnostic agents.…”

Tailoring Gelation Mechanisms for Advanced Hydrogel Applications

“…Michael addition [15,70,71] Thiol-ene addition [16,68,69] Diels-Alder [4 + 2 ] cycloaddition [17,[59][60][61] Inverse-electron demand Diels-Alder cycloaddition [2,[62][63][64][65][66] Disulphide bond formation [18] Hydrazone bond formation [19] -Free-radical polymerization [137][138][139][140][141][142][143] -Polyphenol-based reactions [95][96][97][98][99][100][101] Reactions between polymer chains and nanoparticles -Thiol-ene addition [20,21] -Free-radical polymerization [22] -EDC coupling [23] -Coordinate covalent bond formation [84] Electrostatic interactions Ion-polymer interactions [24][25][26][27][28][29] Polymer-polymer interactions [31,32] Other noncovalent interactions Polymer-polymer interactions [33,…”

A High Loading and Recyclable Pentaerythritol Supported Imidazolidin-4-one Catalyst for Enantioselective Diels–Alder Reactions

“…Pentaerythritol is a well known, cheap, atoxic, widely used chemical raw materials, and it is considered to be ideal building blocks in many areas of materials chemistry [32][33][34] and in the synthesis of dendrimers [35][36][37]. Because of its low molecular weight and its special molecular structure, the loading capacity of pentaerythritol is higher than many other kind of supports such as traditional polymer support [10-12, 14, 16, 22], ionic liquid [17][18][19][20] and tetraarylphosphonium salt [28,29].…”